Age-related macular degeneration (AMD) is a highly prevalent, late-onset complex disorder caused by a combination of interacting genetic and environmental factors. Recent studies have identified several Mendelian loci, most notably those encoding proteins of the complement system, which are highly associated with the development of AMD. These loci currently explain between 50-70% of the disease, thus other causal factors most certainly participate in the disease development. Indeed, multiple lines of evidence suggest a role for various environmental factors in AMD. It has been proposed, for example, that diet, smoking, and photochemical damage increase oxidative stress, thereby contributing to development of AMD. These environmental factors act through non-Mendelian genetic mechanisms, including epigenetic regulation of gene expression and damage to mitochondrial DNA (mtDNA), which have been documented in various late-onset complex traits. None of these disease mechanisms has been comprehensively studied in AMD. The major goal of this proposal is to test the hypothesis that the non-Mendelian genetic mechanisms such as copy number variation of genes, epigenetic regulation of gene expression and somatic variation in mtDNA play a significant role in AMD. To investigate this hypothesis, we will utilize a unique repository comprised of 4,000 extensively characterized (both clinically and genetically) human donor eyes and advanced methods of genetic analyses to address the following specific aims: 1) refinement of our knowledge relating to AMD endo- phenotypes and genotype/phenotype correlation by enhanced phenotyping of AMD cases using advanced image analysis; 2) determination of specific genes/loci where copy number variation is associated with AMD; 3) assessment of epigenetic regulation of gene expression in the development of AMD and; 4) assessment of the role of acquired, somatic variation in mtDNA in susceptibility to AMD. The discovery of additional genetic and environmental causes of AMD will contribute important new information pertaining to disease etiology, and will reveal potential new surrogate biomarkers and diagnostic tests. More importantly, the proposed project will likely provide for new pharmacological targets for the treatment of this extremely prevalent and devastating disorder.